Transcript Pharmacology药理学

Gastrointestinal drugs
Weiwei HU
Phone: 0571-88208226
E-mail:[email protected]
1.Hepatic, pancreatic and
biliary disorders
2. Acid-peptic disorders
3.Gastrointesinal motility
disorders
4. Inflammatory bowel diseases
Gastrointestinal drugs
1. Drugs used for acid-peptic
disorders
2. Modulators of gastrointestinal
functions
1. Acid-peptic disorders
1) Peptic ulcer disease (PUD, 消化性溃疡)
2) Gastroesophageal reflux disease (GERD)
3) Drug-induced mucosal injury, especially by
non-steroidal anti-inflammatory drugs (NSAIDs)
4) Pathologic acid-hypersecretory conditions (e.g.
Zollinger-Ellison syndrome)
5) Acute stress ulcers
1)
The feature of peptic ulcer disease:
High incidence, Recurrence frequently, Drug
treatment is the main way
Symptoms:
Upper abdominal burning or hunger pain
Emesia (呕吐), belching (嗳气)
Ulcer complication
Ulcer bleeding (出血)
Ulcer perforation (穿孔)
Pyloristenosis (幽门狭窄)
Canceration (癌变)
2) Gastroesophageal reflux disease (GERD)
Abnormal reflux in the esophagus
3) Drug-induced mucosal injury, especially by
non-steroidal anti-inflammatory drugs (NSAIDs)
4) Pathologic acid-hypersecretory conditions (e.g.
Zollinger-Ellison syndrome)
Tumor
Gastrin
Gastic acid
Peptic ulcer
5) Acute stress ulcers
2. Gastric acid secretion and regulation
Gastric cells of mucosa
(1) Surface epithelial cells (secrete mucus)
(2) Mucus neck cells (secret mucus and are the
source of proliferating cells);
(3) Chief cells (secret pepsinogens)
(4) G cells (release gastrin in the antrum);
(5) Parietal cells in the gastric fundus ( secrete
HCl and intrinsic factor)
2. Gastric acid secretion and regulation
(the proton pump)
Basolateral membane
Mucus-bicarbonate barrier
Helicobacter pylori infection
2.Pathogenesis of peptic ulcers
Aggressive factors
Gastric acid
Pepsin
Helicobacter pylori
Defensive factors
Mucus
bicarbonate
Mucosa
Pathogenesis of peptic
ulcers
(1)Increased gastric
acid secretion
Treatment approaches
(1)Reducing secretion of
gastric acid or neutralizing
the acid
(2)Infection with gramnegative Helicobacter
pylori
(2)Eradicating H.
pylori infection
(3)Inadequate mucosal
defense against gastric
acid
(3)Protecting the gastric
mucosa from damage
3.Drugs used for peptic ulcers
(1) Antacids: neutralizing the acid
(2) Drugs suppressing gastric acid secretion
①Muscarinic receptor antagonists
②H2 receptor antagonists
③Gastrin receptor antagonists
④ H+-K+-ATPase inhibitors (proton pump
inhibitors)
(3)Antimicrobial drugs (Helicobacter pylori)
(4)Mucosal protective drugs
 (1) Antacids
(Weak bases)
Chemistry of antacids:
Salts of aluminum (aluminum hydroxide) ,
Salts of magnesium (carbonate, hydroxide,
trisilicate) , aluminum magnesium carbonate
(Al2Mg6(OH)16CO3·4H2O)
calcium(carbonate)
sodium (bicarbonate)
 (1) Antacids
(the proton pump)
Mechamism of action
×
Antacids
(1) Antacids
1. Pharmacological effect
Neutralizing gastric acid, diminish gastric acidity and
inactivate pepsin（胃蛋白酶）activity
The effect depends on the dose and dosing frequency.
Starting effect within 5-15 min after taking the drugs.
2. Clinical uses
Commonly used for acid-peptic disorders (peptic ulcer),
gastritis, duodenitis.
3. Adverse effects
(1) Constipation and stomach cramp (salt of aluminum)
(2) Diarrhea (salt of magnesium )
Combination products such as maalox
(3) Hypercalcium which can cause renal failure (Calcium)
(4) Hypernatremia (sodium-containing antacids)
All antacids are generally regarded as safe in pregnancy.
4. Drug interactions
Avoid concurrent administration of antacids and a variety of
drugs .
(1) Affect rates of dissolution and absorption, bioavailbility,
and renal elimination of many drugs
(2) By binding to drugs (for example, tetracycline四环素),
form insoluble complexes that are not absorbed
Adminstration and dosage
(1) Take antacids after meals and at bedtime
(2) Should taken continuously for a long time
(3) To help avoid or reduce drug interaction, other
medication should not be taken within 1-2 hours
of taking an antacids
(2) Drugs affecting gastric acid secretion
② H2 receptor antagonists
Cimetidine
H3C
CH2SCH2CH2NHCNHCH3
HN
N
N
CN
cimetidine
×
(Proton pump)
Mechamism of action
Cimetidine
1. Pharmacological effect
Blocking H2 receptors, decreasing H+ secretion
2. Clinical uses
1) Duodenal and gastric ulcer
2) Zollinger-Ellison syndrome,
3) Acute stress ulcers
4) Gastroesophageal reflux disease (heartburn)
Cimetidine
3. Adverse effects
(1) common side effects: constipation, diarrhea, tiredness,
muscular pain, etc.
(2) CNS effects: headache, dizziness, confusion,
hallucination, etc. (elderly, long-term uses)
(3)Endocretion effects: antiandrogen （ 抗 雄 激 素 ） ,
gynecomastia, galactorrhea,reduced sperm count, and
male sexual dysfunction
4. Drug interactions
Inhibiting hepatic P450, raising plasma concentrations of
warfarin, phenytoin, diazepam, propranolol, quinidine
and theophylline
5. Elimination
Urinary excretion is the principal route of
elimination of cimetidine, the dose should be
modified in patients with renal impairment.
Other H2 receptor antagonists
Ranitidine
4-10 times more potent than cimetidine
Minimal side effects, weakly inhibiting CYP
Famotidine
7-10 times more potent than ranitidine, but no
inhibiting CYP
Nizatidine
Bioavailability is near 100%, principally eliminated
by kidney
(2) Drugs affecting gastric acid secretion
③H+-K+-ATPase inhibitors
(proton pump inhibitors)
奥美拉唑
Omeprazole
OCH3
H3C
CH3
N
CH2
O
OCH3
N
S
N
H
Omepranzole
×
(the proton pump)
Omeprazole
 1. Pharmacological effects
 (1) Inhibiting gastric acid secretion by various stimuli
(histamine, gastrin, aspirin, ethanol, stress)
 (2) Inhibiting H. pylori
 (3) protection for gastric mucosa
 2. Clinical uses
 (1) Highly effective for duodenal and gastric ulcer:
relieving symptoms, promoting healing of ulcers, with
antimicrobial regimens to eradicate H. pylori
 (2) Gastro-esophageal reflux disease
 (3) Zollinger-ellison syndrome
Omeprazole
 3. Adverse effects
 (1) Side effects: nausea, headache, diarrhea, constipation and
rash occur but are uncommon
 (2) Increase of gastric carcinoid tumor: prolongated
hypochlorhydria and secondary hypergastrinemia (only
found by animal experiments)
 (3) Others: gynecomastia (男性乳房发育), hypersensitivity
 4. Drug interactions
 It is metabolized by hepatic P450;
 Inhibiting hepatic P450, raising plasma concentrations of
warfarin, phenytoin, diazepam, etc.
Others proton pump inhibitors
M receptor antagonists
 Non-selective: atropine (block M3 receptor
in Parietal cells, block M1 receptor in
ganglion, block M receptors in ECL and G
cells), seldom use now.
 Selective: pirenzepine (block M1 receptor)
(3) Mucosal protective drugs
Effects: Protecting the gastric and duodenal
mucosa from damage by acid and pepsin
Misoprostol 米索前列醇
Sucralfate 硫糖铝
Colloidal bismuth subcitrate 胶体次枸橼
酸铋
(3) Mucosal protective drugs
Misoprostol 米索前列醇
O
O
CH3
OCH3
OH
HO
A prostaglandin E1 analogues
(3) Mucosal protective drugs
Misoprostol 米索前列醇
1. Pharmacological effects
Inhibiting gastric acid secretion
Promoting mucus and HCO3- secretion, and mucosal repair
2. Clinical uses
Only approved for the prevention of NSAIDs-induced gastric
Ulcer.
3. Adverse effects
Side effects (13%): abdominal pain, diarrhea, headache, nausea
etc.
Contraindicated in pregnancy women
(Abortifacient 堕胎 property)
(3) Mucosal protective drugs
Sucralfate
A sulfated disaccharide（二糖） complex of aluminum hydroxide
(3) Mucosal protective drugs
Sucralfate
1. Pharmacological effects
1) Binding to tissue surface and forms a protective barrier
2) Enhancing cell restitution and re-epithelization.
3) Weakly inhibiting H.Pylory growth.
4) Promote PGE2 production
5) Binding to pepsin and then reduce its activity
2. Clinical uses and Adminstration
Peptic ulcers, but with the more effective agents (proton pump
inhibitors. Gastro-esophageal reflux disease. H pylori infection.
Take sucralfate 1 hour before meals
Four times a day before meals and at bedtime
3. Adverse effects
Constipation occurs in 2% due to the aluminum salt, not together with
alkaline agents
(3) Mucosal protective drugs
Colloidal bismuth subcitrate (CBS 胶体次枸橼酸铋)
1. Pharmacological effects
1) Probably coats ulcers and erosions, creating a
protective layer against acid and pepsin
2) Inhibit pepsin activity, stimulate prostaglandin,
mucus, and bicarbonate secretion
3) Have direct antimicrobial activity against H pylori
Bismuth Compounds
2. Clinical uses
1) Peptic ulcers, chronic gastritis, duodenitis,
functional dyspepsia
2) Used in multidrug regimens for the eradication of H
pylori infection.
3. Adverse effects
Causes blackening of the stool, which may be
confused with gastrointestinal bleeding
Bismuth toxicity resulting in encephalopathy
(ataxia, headaches, confusion, seizures).
(3) Mucosal protective drugs
Smectite
1) Bind to the glycoprotein in the mucus to increase its
coverage ability, enhancing cell restitution,
antimicrobial activity against H pylori.
2) Use for acute or chronic diarrhea and ulcer.
(4) Antimicrobial drugs
(for Helicobacter pylori)
1. Anti-ulcer drugs
H+-K+-ATPase inhibitors; bismuch ; sulralfate
Weaker, combined with antimicrobial drugs
2. Antibiotics
metronidazole (甲硝唑); amoxicillin (阿莫西林);
tetracycline (四环素);
gentamicin (庆大霉素);
clarithromycin (克拉霉素)
The best treatment regimen consists of a 10–14 day
regimen of "triple therapy":
Program 1
1) A proton pump inhibitor twice daily,
2) Clarithromycin 500 mg twice daily,
3) Amoxicillin 1 g twice daily.
For patients who are allergic to penicillin, metronidazole
500 mg twice daily should be substituted for amoxicillin.
Program 2
1) Bismuth subsalicylate (2 tablets; 262 mg each),
2) Tetracycline (500 mg),
3) Metronidazole (250 mg), each taken four times
daily for 14 days.
For patients with resistant infections,
"quadruple therapy”
1) A proton pump inhibitor twice daily
2) Bismuth subsalicylate (2 tablets; 262 mg each),
3) Tetracycline (500 mg),
4) Metronidazole (250 mg), each taken four times daily
for 14 days.
Gastrointestinal drugs
1. Drugs used for acid-peptic
disorders
2. Modulators of gastrointestinal
functions
Abnormalities of gastrointestinal functions
Nausea and vomiting
Diarrhea
Constipation
Modulators of gastrointestinal functions
1. Antiemetic drugs
2. Prokinetic drugs
3. Anti-diarrheals
4. Laxatives
Antiemetic drugs
There are various sources of input to the vomiting center:
1.
2.
3.
4.
5.
The chemoreceptor trigger zone at the base of the fourth ventricle has numerous
dopamine D2 receptors, serotonin 5-HT3 receptors, opioid receptors,
acetylcholine receptors, and receptors for substance P. Stimulation of different
receptors are involved in different pathways leading to emesis, in the final
common pathway substance P appears involved.
The vestibular system, which sends information to the brain via cranial nerve
VIII (vestibulocochlear nerve), plays a major role in motion sickness, and is rich
in muscarinic receptors and histamine H1 receptors.
The Cranial nerve X (vagus nerve) is activated when the pharynx is irritated,
leading to a gag reflex.
The Vagal and enteric nervous system inputs transmit information regarding the
state of the gastrointestinal system. Irritation of the GI mucosa by chemotherapy,
radiation, distention, or acute infectious gastroenteritis activates the 5-HT3
receptors of these inputs.
The CNS mediates vomiting that arises from psychiatric disorders and stress
from higher brain centers.
Antiemetic drugs
1. H1 antagonists: sedative effect, antiemetic effect, use for
motion sickness and Meniere disease.
2. M receptor antagonists: scopolamine, use for motion
sickness.
3. D receptor antagonists: chloropromazine, thiethylperazine
(硫乙拉嗪).
4. 5-HT3 receptor antagonists: ondansetron, granisetron,
tropisetron, et al. Use for vomiting induced by
chemotherapy for cancer, but not for motion sickness.
Prokinetic drugs
NANC
neuron
Post-ganglionic primary
motor neuron
Cholinergic
neuron
GI tract smooth muscle cells
prokinetic drugs
Metoclopramide 甲氧氯普胺
Mechanism of action
1) Block D2 receptor, to stimulate 5-HT4 receptors and
enhance coordinated transmission in cholinergic nerve
plexues
2) An dopaminergic neuron antagonist in the central nervous
system; at higher doses, 5-HT3 antagonist activity may also
contribute to the anti-emetic effect.
Clinical uses
1) Used for treatment of diabetic gastroparesis
2) Used for the prevention of nausea and vomiting associated
with cancer chemotherapy or occurring post-operatively.
Metoclopramide
Adverse effects
1) Fatigue, dizziness, faintness
2) Various extrapyramidal syndromes caused by its central
anti-dopaminergic activity.
Parkinsonism (reversible)
tardive dyskinesia (irreversible)
3) Increased serum prolactin levels (chronic uses)
prokinetic drugs
Domperidone 多潘立酮
Mechanism of action
A peripherial dopamine antagonist, has no procholinergic
effects
Adverse effects
Has few side effects because it can not cross the BBB
Increased serum prolactin levels ( 6% of patients)
Rare cases of prolongation of QT interval.
Modulators of gastrointestinal functions
Anti-diarrheals
Diarrhea
1) An increase in the active
secretion, or an inhibition of
absorption
2) Abnormally high motility
Modulators of gastrointestinal functions
Anti-diarrheals
1. Antimotility drugs
2. Astringents
3. Absorbants
Anti-diarrheals
Antimotility drugs:
Mechanisms: Agonists for  receptors in GI
tract
(1) Opium preparation
(2) Diphenoxylate 地芬诺酯
Diphenoxylate dose not cross the blood-brain-barrier as easly as
most opioids do and is relatively selective for peripheral opioid
receptors. Has CNS effects at larger doses)
Anti-diarrheals
Antimotility drugs:
(3) Loperamide 洛哌丁胺
It is two to three times potent than
diphenoxylate, and its action is more rapid
in onset and more prolonged.
Use for acute or chronic diarrhea but not
induced by infection.
It has less CNS or cardiovascular effects .
Anti-diarrheals
Astringents:
Mechanism: astriction
(1) Tannalbin 鞣酸蛋白
(2) Bismuch subsalicylate; bismuch
subcarbonate (铋制剂)
Absorbants：
(1) Medical charchol 药用炭（活性炭）
(2) Agysical 矽炭银
Modulators of gastrointestinal functions
Laxatives
Constipation
An decrease in the active
secretion, or an enhancement
of absorption
Treatment
1) Increase the intake of fluids and dietary fiber
Regular exercise
2) Laxatives
3) Physical intervene
Modulators of gastrointestinal functions
Laxatives
1. Contact laxatives （接触性、刺激性泻药）
2. Osmotic laxatives （渗透性泻药）
3. Emollient Laxatives （润滑性泻药）
4. Bulk-forming Laxatives （膨胀性、容积性泻药）
Laxatives
1. Contact laxatives （接触性泻药）
Phenolphthalein 酚酞
( No longer used because of concerns about carcigenicity)
Bisacodyl 必沙可啶
(It is active after deacetylation, stimulating enteric nerves to cause
colonic mass movements; increases fluid and NaCl secretion. )
Laxatives
1. Contact laxatives （接触性泻药）
Anthraquinones 蒽醌类（中药成分）
promote colon movements
Cascara
（鼠李皮）
Senna
（番泻叶）
Rhubarb
（大黄）
Laxatives
2. Osmotic laxatives （渗透性泻药）
1) Salt laxatives: magnesium sulfate 硫酸镁;
sodium sulfate 硫酸钠；
These agents contain ions that are only slowly absorbed from
the intestine. These ions retain fluid in the bowel lumen and
cause a large volume of fluid to enter the colon.
magnesium sulfate
Laxatives
2. Osmotic laxatives （渗透性泻药）
2) Lactulose 乳果糖;
In the small bowel, it is resistant to hydrolysis and has
an osmotic effect.
In the large intestine, lactulose is acted upon by the
endogenous flora with the production of lactic acid,
Lactic acid also has an osmotic effect.
It is used to reduce ammonia blood
levels in the prevention and treatment of
hepatic encephalopathy
3. Emollient Laxatives （润滑性泻药）
Liquid petrolatum
( Lubricate the fecal mass, prevent
excessive dehydration of the material ,
and may inhibit water reabsorption
by coating the gut wall)
4. Bulk-forming Laxatives （膨胀性、容积性泻药）
Celluloses: used for functional constipation